Thalidomide is effective for treating the toxic and inflammatory manifestations of erythema nodosum leprosum (ENL), a complication of the antimicrobial treatment of multibacillary leprosy. Apparently, antimicrobial therapy releases inflammatory mycobacterial products, and thalidomide blocks the resulting acute inflammatory response. In the laboratory, thalidomide selectively inhibits production of tumor necrosis factor-alpha, (TNF- ) a monocyte product which produces fever, shock, toxicity and cachexia, and which may be responsible for the toxic manifestations of ENL. Tuberculosis is a related chronic, intracellular mycobacterial infection, that also engenders immunopathologic host responses, e.g. caseous necrosis. TNF may contribute to the fever and cachexia of some tuberculosis patients, as well as to tissue damage and necrosis in localized lesions. Although toxic tuberculosis patients may benefit from corticosteroid therapy at initiation of chemotherapy, thalidomide may offer a more selective, less toxic means of modulating the host response. Preliminary data from our laboratory and others show enhanced TNF production in tuberculosis. In the laboratory, thalidomide suppresses TNF production in peripheral blood monocytes of patients with tuberculosis. Thus we hypothesize that thalidomide may modulate toxic host responses in patients receiving chemotherapy for tuberculosis. Similarly, serum TNF and TNF production by peripheral blood monocytes are elevated in AIDS patients and may be responsible for toxicity, fever and wasting. Elevated circulating TNF is also found in children with AIDS and progressive encephalopathy. AIDS patients also commonly experience severe and prolonged infection with mycobacteria, which may result in additional TNF production. While producing undesirable symptoms, TNF may also play a role in the control of viral infection. However, for HIV, most data point to TNF augmenting viral replication. TNF enhancement of viral infection would be likely to lead to the progression of immunodeficiency. We suggest that modulating TNF in HIV infection would be beneficial in controlling HIV replication, in modifying toxic symptoms of HIV and mycobacterial infection that are TNF mediated, and in limiting progression of immunodeficiency related to HIV replication.